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is a significant concern for physicians. Central- V2 i9 s/ \% V4 P
precocious puberty (CPP), which is mediated: p, r6 L$ E: Q
through the hypothalamic pituitary gonadal axis, has2 B; S4 ^! S; f
a higher incidence of organic central nervous system- u: u5 `4 @3 |# }# r6 P
lesions in boys.1,2 Virilization in boys, as manifested
/ e' y. k; \; V& d0 H z, m. l( w% ^by enlargement of the penis, development of pubic& ]% A5 \1 C4 C
hair, and facial acne without enlargement of testi-
9 }$ K! ?0 B2 m5 gcles, suggests peripheral or pseudopuberty.1-3 We
3 d; i( R9 C2 z; u: @ @; @& \report a 16-month-old boy who presented with the
; J: ~! R' z8 s5 [$ s& Aenlargement of the phallus and pubic hair develop-
% \( B! w: C; a4 _+ C/ |ment without testicular enlargement, which was due: M* B3 Z7 {. z/ x. `/ }- [+ g
to the unintentional exposure to androgen gel used by
2 v y6 ~# I* [; G0 Z! N+ athe father. The family initially concealed this infor-6 J8 ~1 Z3 H1 _: L, P( }
mation, resulting in an extensive work-up for this2 `( e; h) i4 Y! t! P- N
child. Given the widespread and easy availability of
9 d* v8 ]: H' { R8 M, z: B( r) \testosterone gel and cream, we believe this is proba-/ {9 ~1 M% F4 b, D
bly more common than the rare case report in the
# t/ a& z" g: ^+ f& jliterature.45 Y, h" N/ t1 Z
Patient Report
8 G: h7 n( B# K( SA 16-month-old white child was referred to the
; Z3 N8 `+ _( j. J1 zendocrine clinic by his pediatrician with the concern
( k! O6 B& h( ?- w& Vof early sexual development. His mother noticed) m) P/ V9 g' x, Q
light colored pubic hair development when he was( [4 _* V( w( S5 e+ U$ u+ k* |% U
From the 1Division of Pediatric Endocrinology, 2University of
) y* ?" D j5 i" i6 }5 ISouth Alabama Medical Center, Mobile, Alabama.8 B M4 ?! X! y" ]: H5 |
Address correspondence to: Samar K. Bhowmick, MD, FACE,% q6 `7 M) l1 f* |
Professor of Pediatrics, University of South Alabama, College of
5 k; Y2 d. @- l9 sMedicine, 2451 Fillingim St. Mastin 212, Mobile, AL 36617-2297;
' z1 a+ K3 _; s7 h; Te-mail: [email protected].
: h+ n2 _! z2 ~& B, yabout 6 to 7 months old, which progressively became9 |% ]! _% t K, T* L
darker. She was also concerned about the enlarge- V$ O$ |+ Z+ t# N/ }, k0 l& K4 [
ment of his penis and frequent erections. The child
' G, |+ G7 h6 |was the product of a full-term normal delivery, with) X. |+ H; {' k% n- @5 b3 X
a birth weight of 7 lb 14 oz, and birth length of9 L& N* E0 p7 l& v4 V
20 inches. He was breast-fed throughout the first year( z# x5 d8 y) r$ _# ~, G( W
of life and was still receiving breast milk along with
. e9 U& P. c9 {4 ~solid food. He had no hospitalizations or surgery,) o( z/ s1 _3 ~7 ]# I( f
and his psychosocial and psychomotor development7 {6 m6 ^9 M5 I/ x; i
was age appropriate.; }* ?' j* |' L! C! y
The family history was remarkable for the father,
; U- o' M9 E/ |( vwho was diagnosed with hypothyroidism at age 16,# [4 \2 k9 {: K/ H
which was treated with thyroxine. The father’s
( a: x2 P! x: q8 e* eheight was 6 feet, and he went through a somewhat
1 E# S6 i+ X! Learly puberty and had stopped growing by age 14.
' Y6 a& n7 ^8 k% HThe father denied taking any other medication. The
0 C( O% u* p, k! p. ?! L4 Ychild’s mother was in good health. Her menarche
7 [. _# i: z. w( y' ?5 n# Rwas at 11 years of age, and her height was at 5 feet1 p( P, u c6 Q* P4 N, V9 F
5 inches. There was no other family history of pre-
A! o8 C. y! J2 m/ P4 y) _; b% ^' xcocious sexual development in the first-degree rela-9 i& S( M+ F: r6 E
tives. There were no siblings.
- X2 S0 ]* w% Y& X- c9 _Physical Examination0 n; E+ q* Z1 h2 ]" B
The physical examination revealed a very active,
' J: E9 t: d u; aplayful, and healthy boy. The vital signs documented) @0 w4 a, a$ c6 W
a blood pressure of 85/50 mm Hg, his length was
" K: I: e7 w3 M. p90 cm (>97th percentile), and his weight was 14.4 kg
$ ]' O+ E% |6 P. m(also >97th percentile). The observed yearly growth
: n% Q; y3 _% V: A+ mvelocity was 30 cm (12 inches). The examination of7 K7 I I+ V9 P7 a* I
the neck revealed no thyroid enlargement.
% A* {9 U# ?% e, Q' LThe genitourinary examination was remarkable for
* D! }* ?8 f+ _enlargement of the penis, with a stretched length of
3 r& c" k) C& |# i7 [+ O9 v8 cm and a width of 2 cm. The glans penis was very well
$ R1 y! U w4 R! U2 }; V; Ndeveloped. The pubic hair was Tanner II, mostly around
; ?8 E9 ~0 E% ], d x4 a% p540
' ]/ ~" H+ O/ f! U! S0 X/ A& bat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from, V$ m& A) @! k6 [1 m2 D
the base of the phallus and was dark and curled. The
9 ?- ]. u; @* A, l/ \6 g9 \; {testicular volume was prepubertal at 2 mL each.
, l" `+ S1 l5 p, @) wThe skin was moist and smooth and somewhat6 k8 K+ T3 M; K' E9 a( O/ `' m0 N
oily. No axillary hair was noted. There were no
. |% s. _$ f" R S# t' }abnormal skin pigmentations or café-au-lait spots.! ^& L6 |& m" t0 g
Neurologic evaluation showed deep tendon reflex 2+# V. N8 T! K. ?, X# q4 \
bilateral and symmetrical. There was no suggestion) V3 F6 d: w, M1 v. a+ c( ~/ T
of papilledema.
4 w4 X1 V, P3 k: m$ h0 BLaboratory Evaluation ?9 w+ `- W' X# _4 s1 I& C
The bone age was consistent with 28 months by
/ Y$ T k+ S2 `5 `- w/ ` ^1 Rusing the standard of Greulich and Pyle at a chrono-. l7 {9 K# X, H5 R. J% f
logic age of 16 months (advanced).5 Chromosomal- y. _8 p3 A0 i
karyotype was 46XY. The thyroid function test. R9 }+ K4 l4 b. |; S4 b4 |) S
showed a free T4 of 1.69 ng/dL, and thyroid stimu-% Q9 G+ o4 T$ {- _) o; P9 v( G n# O. e
lating hormone level was 1.3 µIU/mL (both normal).
. O8 t7 c4 ?+ \3 N5 pThe concentrations of serum electrolytes, blood4 Z. K/ U' }0 o4 R
urea nitrogen, creatinine, and calcium all were
! J( H5 v$ r" w- x$ pwithin normal range for his age. The concentration8 d4 Q* ~$ E4 j- q( w2 E1 G% D
of serum 17-hydroxyprogesterone was 16 ng/dL
& G6 h2 c9 r2 M4 S+ \+ R0 K(normal, 3 to 90 ng/dL), androstenedione was 20" o8 Z( P# _! Q% B8 E, e9 ]- N
ng/dL (normal, 18 to 80 ng/dL), dehydroepiandros-' a. A; \% n- x( y, b( Y3 h) ^ W
terone was 38 ng/dL (normal, 50 to 760 ng/dL),
7 j) _4 ^& z6 }0 A8 Vdesoxycorticosterone was 4.3 ng/dL (normal, 7 to* J# z2 q3 W; Q. X9 A0 i s$ l6 O
49ng/dL), 11-desoxycortisol (specific compound S)
& Y. I5 w! @5 z$ F2 @: n t" xwas 43 ng/dL (normal, 10 to 156 ng/dL), serum cor-
9 ~% v& h0 r; [. n2 ], stisol was 7.6 µg/dL (normal, 2.8 to 23 µg/dL), total0 R# i" R1 ]' e* ~: c" T
testosterone was 60 ng/dL (normal <3 to 10 ng/dL),5 M B2 ?) A, C7 e8 K$ [* j# p
and β-human chorionic gonadotropin was less than9 Z- j" H/ |) u/ v
5 mIU/mL (normal <5 mIU/mL). Serum follicular6 Q: [* G$ S1 Y+ j2 G
stimulating hormone and leuteinizing hormone
5 {5 t! \% }$ Uconcentrations were less than 0.05 mIU/mL
' s5 |; g% `) E+ `& F0 c# y(prepubertal).& K4 R% M- W& n8 J+ h! ~6 o# `0 a
The parents were notified about the laboratory
1 i5 I" R7 C9 b8 Dresults and were informed that all of the tests were
8 U# P+ S& k: F0 nnormal except the testosterone level was high. The8 R t2 e9 H# b, b( |
follow-up visit was arranged within a few weeks to- b1 D' Z- J6 C
obtain testicular and abdominal sonograms; how-
# }" K, O# V6 N4 lever, the family did not return for 4 months.
7 ^& _. o( }+ E3 KPhysical examination at this time revealed that the
% |/ r: A% C3 Z6 A& Y4 Y- s0 Wchild had grown 2.5 cm in 4 months and had gained
R& i% Q4 v& W2 kg of weight. Physical examination remained" L9 E4 A* A6 R7 ]' s7 r- U' [
unchanged. Surprisingly, the pubic hair almost com-
/ U4 b$ K: b$ f4 O6 n4 h2 kpletely disappeared except for a few vellous hairs at3 w& z2 [7 B1 l2 e/ [, J
the base of the phallus. Testicular volume was still 27 J, ^+ q5 H& x" ~; v
mL, and the size of the penis remained unchanged.
- B6 z8 d/ y# y4 eThe mother also said that the boy was no longer hav-, S! P7 t7 S* P
ing frequent erections.
! Y- m/ V$ t0 d5 R+ SBoth parents were again questioned about use of
5 t [5 G0 z# x$ Z- W2 B! f0 Cany ointment/creams that they may have applied to
& e& J I! o! E2 u2 {the child’s skin. This time the father admitted the; _& Y6 Y3 z& ?! G1 [) p
Topical Testosterone Exposure / Bhowmick et al 541' N- v% O* d, q' w8 n3 h
use of testosterone gel twice daily that he was apply-
" e/ s9 f3 C4 G6 J. ]- o" V. L$ ?ing over his own shoulders, chest, and back area for
4 y1 |5 ]7 X, ca year. The father also revealed he was embarrassed& K0 |1 Q% ]# J
to disclose that he was using a testosterone gel pre-
& F, ~0 H. ?$ c9 }$ _; }) ascribed by his family physician for decreased libido9 v9 X5 r9 ?5 F. \
secondary to depression.8 i4 A8 J l0 s) R! ]
The child slept in the same bed with parents.
( }+ k3 z1 i3 ^The father would hug the baby and hold him on his
& e; |2 z3 z* }8 {; Cchest for a considerable period of time, causing sig-
& Z7 q6 a" R/ ?nificant bare skin contact between baby and father.; {4 _* m$ V6 Z* D
The father also admitted that after the phone call,( d- E Z3 ^) H' A
when he learned the testosterone level in the baby
0 z% `* B/ N. x* w8 C+ Z2 bwas high, he then read the product information
2 N5 i# L) ^) {$ y8 ?8 o+ Dpacket and concluded that it was most likely the rea-
( e* _ @1 b7 l: l: m; |son for the child’s virilization. At that time, they& v8 N; }% u0 j+ X
decided to put the baby in a separate bed, and the ?- S; |' D* X8 r# [- c' I
father was not hugging him with bare skin and had
8 l/ ~& \! R/ Gbeen using protective clothing. A repeat testosterone
, R0 M6 h1 I2 R/ k: _test was ordered, but the family did not go to the6 `" P: U2 t( A- [; I+ s/ W8 _, K+ i
laboratory to obtain the test.
, L9 z4 _" e. Y; n( i! ?Discussion
1 j0 `9 R- h( r1 |* D jPrecocious puberty in boys is defined as secondary( W7 P) E6 J! `( L5 e T% I
sexual development before 9 years of age.1,4# r2 O' t& j. O
Precocious puberty is termed as central (true) when) n& ~- W# ]' h7 }" O5 {) X
it is caused by the premature activation of hypo-
$ ^6 r0 a+ }3 g5 Q5 p+ Lthalamic pituitary gonadal axis. CPP is more com-% j0 n5 `) D) T/ v" x6 B9 \' Y
mon in girls than in boys.1,3 Most boys with CPP1 U1 D& Z$ h n1 G+ B8 e: K3 J& v
may have a central nervous system lesion that is
; y" w8 S3 E/ |* U3 bresponsible for the early activation of the hypothal-
; Z1 h; M- m% g1 f' Iamic pituitary gonadal axis.1-3 Thus, greater empha-
: J C7 m9 v# }; M& {" k. A2 _2 Hsis has been given to neuroradiologic imaging in
1 {6 p3 o) ]0 aboys with precocious puberty. In addition to viril-
9 p% F, u# e# s# m/ Qization, the clinical hallmark of CPP is the symmet-
- k8 ^/ E8 V+ _" f" t1 l; grical testicular growth secondary to stimulation by
: k0 ~, u: Q5 b3 G3 C7 N8 g- w4 Agonadotropins.1,3
8 }: E. K. h* G, k8 aGonadotropin-independent peripheral preco-
" X1 K4 M# K' l8 `# Hcious puberty in boys also results from inappropriate. l) ^4 M3 V8 R; C. n9 I
androgenic stimulation from either endogenous or2 L- g/ }7 }3 ~( C3 r
exogenous sources, nonpituitary gonadotropin stim-
7 I; b" j* i0 ]ulation, and rare activating mutations.3 Virilizing9 o/ k5 D% m$ S
congenital adrenal hyperplasia producing excessive% {) P8 U& X: o T5 ]: H# u
adrenal androgens is a common cause of precocious
: }. ^, L( m- b! ~, Tpuberty in boys.3,4
" Q( K8 t r: G/ n5 i1 EThe most common form of congenital adrenal
2 D' @, G1 d, ~. k9 i8 vhyperplasia is the 21-hydroxylase enzyme deficiency.; n, E8 T, s2 R1 h$ j. i( ]
The 11-β hydroxylase deficiency may also result in
9 H( d1 a' z0 W/ Y; `+ s, U# nexcessive adrenal androgen production, and rarely,2 G0 K3 v$ m: k F
an adrenal tumor may also cause adrenal androgen `1 R/ F4 R+ ^) F
excess.1,3
& M- s5 J) \1 P1 N. hat University of Manchester Library on May 25, 2015 cpj.sagepub.com Downloaded from
! I: V5 L; z$ K: b542 Clinical Pediatrics / Vol. 46, No. 6, July 2007+ e# |2 F7 Y* p- B8 u
A unique entity of male-limited gonadotropin-) G- H' S8 n! e3 w& G- l8 \
independent precocious puberty, which is also known
4 }7 K" Z5 h4 h) yas testotoxicosis, may cause precocious puberty at a
. k2 @% C8 [# gvery young age. The physical findings in these boys
0 [! f' X% P" q4 ^1 d- \with this disorder are full pubertal development,
I$ O+ P8 j. @" }+ l$ Kincluding bilateral testicular growth, similar to boys
7 B" `9 B: u/ F2 owith CPP. The gonadotropin levels in this disorder( m, V) u5 H/ k. A+ ]- v
are suppressed to prepubertal levels and do not show
7 r. f3 ?; S; Z- [9 epubertal response of gonadotropin after gonadotropin-4 i" t ~$ a3 m' C, x K* W3 X
releasing hormone stimulation. This is a sex-linked
$ K2 T, K2 P6 d) H4 T2 i" n R8 Nautosomal dominant disorder that affects only$ L+ \4 C: I6 I2 \9 e( W( l: K
males; therefore, other male members of the family
4 v* ?4 I% H: @6 V. ^7 t. `may have similar precocious puberty.3
8 I- e1 e( X# I. sIn our patient, physical examination was incon-7 `& {' r' m& K' u' y7 b
sistent with true precocious puberty since his testi-* J% K6 d" O- i' ^! k: p) ?
cles were prepubertal in size. However, testotoxicosis, t) @/ {" A3 |3 x
was in the differential diagnosis because his father
, `7 ^5 o8 i* O% D- ?* ]started puberty somewhat early, and occasionally,+ _- G% w% \2 M# j( u& A5 J: `
testicular enlargement is not that evident in the
' h- [* o; Q/ {7 e# C* }3 Dbeginning of this process.1 In the absence of a neg-1 O. y5 l+ {+ L1 {- |
ative initial history of androgen exposure, our
; y3 p+ u$ b7 y3 ~biggest concern was virilizing adrenal hyperplasia,
& k. Q' e6 d+ d5 d+ s: }either 21-hydroxylase deficiency or 11-β hydroxylase
& Y5 E, K; r' c w& o# O: N4 Q( qdeficiency. Those diagnoses were excluded by find-
; }) b8 @4 Z( W: eing the normal level of adrenal steroids.1 f9 C% l" {9 B$ P5 |7 x$ a6 ?
The diagnosis of exogenous androgens was strongly
2 L$ D! O E5 F2 `1 o' ssuspected in a follow-up visit after 4 months because* A$ @; l9 G1 S0 j# Y# |
the physical examination revealed the complete disap-
8 q1 }9 h% I7 x6 ?3 s, V( T+ i8 xpearance of pubic hair, normal growth velocity, and+ n9 u9 E5 B4 ^# N1 z2 ^6 t( _
decreased erections. The father admitted using a testos-
8 |! ~5 \' {; F. E8 |$ Oterone gel, which he concealed at first visit. He was x0 o( ~6 U, S# Z* h
using it rather frequently, twice a day. The Physicians’
% r& \* O; m3 a+ X( M5 CDesk Reference, or package insert of this product, gel or
% s5 i5 L3 Z N# `cream, cautions about dermal testosterone transfer to7 _ E3 [' {0 i2 e
unprotected females through direct skin exposure.
: |% }9 E: ?" B' Z) Y; ~: XSerum testosterone level was found to be 2 times the
2 m% d& f( K% {4 c" G2 c$ Mbaseline value in those females who were exposed to3 @& u2 R" i0 c7 [. Q9 \. E8 ?
even 15 minutes of direct skin contact with their male
; R% [1 |6 ^. }partners.6 However, when a shirt covered the applica-8 h( K$ d4 k. m/ p
tion site, this testosterone transfer was prevented.4 d0 d) D3 f3 }
Our patient’s testosterone level was 60 ng/mL,/ P* U3 h2 \# V$ x8 E
which was clearly high. Some studies suggest that T% Z3 r6 c3 Z
dermal conversion of testosterone to dihydrotestos-: @# O. j2 f/ v; ^* o5 p. Z5 z" }9 b
terone, which is a more potent metabolite, is more6 [5 T/ g) _9 _+ {, K
active in young children exposed to testosterone3 t# t% ?6 t- H/ [
exogenously7; however, we did not measure a dihy-* k" H6 j6 j0 ~1 J- l" s) [/ d
drotestosterone level in our patient. In addition to4 C2 U$ q: W5 [$ x+ b
virilization, exposure to exogenous testosterone in
" t1 E6 K4 V7 s. U4 T' A1 e" Echildren results in an increase in growth velocity and- }$ b% p" h! [ b
advanced bone age, as seen in our patient.. L7 l7 D, J* O+ A" Q
The long-term effect of androgen exposure during
) J5 o8 o9 D# e& P. v ~ wearly childhood on pubertal development and final
8 ^# k3 i8 s1 k' t- Dadult height are not fully known and always remain; ?4 i M! m3 B, `( y, J/ y
a concern. Children treated with short-term testos-
$ C5 s& k8 D2 _& G8 i$ ^terone injection or topical androgen may exhibit some! r/ i$ ]2 ~# H
acceleration of the skeletal maturation; however, after9 S$ A" f. W+ d( K2 L( ?+ ]
cessation of treatment, the rate of bone maturation
9 R% R \9 Z0 F& r6 xdecelerates and gradually returns to normal.8,9
0 W3 Z. c$ A5 D3 Q# P2 e+ P. }" k" g7 hThere are conflicting reports and controversy4 W3 \% x/ I; H* T$ T/ |
over the effect of early androgen exposure on adult
/ F: ^+ I* B% F5 [# P3 qpenile length.10,11 Some reports suggest subnormal
1 \% v4 t( {$ i, H( i! r9 @0 eadult penile length, apparently because of downreg-# ^+ ~/ f3 \0 g) H
ulation of androgen receptor number.10,12 However,
* s$ Z6 `0 u2 Y/ rSutherland et al13 did not find a correlation between
N* B8 [1 x E. Ochildhood testosterone exposure and reduced adult
9 \1 p5 G3 `. O9 P* u C( Gpenile length in clinical studies.$ K( o) Q% [* U
Nonetheless, we do not believe our patient is
0 z/ a( K+ P9 U# i7 v4 ]" r- vgoing to experience any of the untoward effects from
$ h7 j6 x! O1 ^- f2 L) Itestosterone exposure as mentioned earlier because
2 {& N1 _: b f7 Ythe exposure was not for a prolonged period of time.3 `9 x8 P+ `2 O+ c
Although the bone age was advanced at the time of
( E9 j* ~5 x6 G" b5 ]+ Fdiagnosis, the child had a normal growth velocity at
* q9 Q% X* g! D5 L, I2 Vthe follow-up visit. It is hoped that his final adult* @" n. E8 M5 F4 o1 p) k' f' i, ]6 y
height will not be affected.- K& ^8 ^# [) i+ H x& s1 @
Although rarely reported, the widespread avail-6 \6 a) {6 H$ d5 X! x; U6 i
ability of androgen products in our society may. l* @- M$ u: B/ m% }$ c8 S
indeed cause more virilization in male or female
' n5 x" ?7 C6 { T1 X4 Lchildren than one would realize. Exposure to andro-
: Q4 M% ]8 A& Q( S$ j3 U5 I4 mgen products must be considered and specific ques- G' Q; ~, h; F6 W% R% _
tioning about the use of a testosterone product or
* u0 P6 Y, D& H7 o; vgel should be asked of the family members during
8 J- r1 C- j4 V Othe evaluation of any children who present with vir-: s3 P# s: p" H& N2 I8 Z
ilization or peripheral precocious puberty. The diag-0 w/ ~7 I9 P A0 y
nosis can be established by just a few tests and by
+ V" B8 R, ` ^ C8 N# l; ]% Q% N! nappropriate history. The inability to obtain such a$ @( t) K" a' i2 _ V! G
history, or failure to ask the specific questions, may& Z& D" t0 M* g+ _! C1 @6 ^. ^
result in extensive, unnecessary, and expensive, f, N9 ~4 y# Y# E9 o
investigation. The primary care physician should be2 }! `7 v: h. h" D
aware of this fact, because most of these children
. L. ]. A" N3 N4 n6 n" d3 vmay initially present in their practice. The Physicians’# S1 N" i& B' X, l: x. Z8 q. g
Desk Reference and package insert should also put a
) Z' n; x. |# d! D* h9 ^warning about the virilizing effect on a male or: g/ ~& B! c. Q& j
female child who might come in contact with some-% @1 I* L0 h T$ ?, }+ @/ Y1 L
one using any of these products.
% p) T { k3 r/ S5 VReferences p( {( ^+ i! ]% C! {
1. Styne DM. The testes: disorder of sexual differentiation; m$ `& J$ U9 l, Z3 _4 l
and puberty in the male. In: Sperling MA, ed. Pediatric2 q+ ?3 G! u. k
Endocrinology. 2nd ed. Philadelphia, PA: WB Saunders;
9 c& v$ e2 s, }( T2002: 565-628.! Y" M% K8 C% o3 r' G4 \" B
2. Rivarola M, Belgorosky A, Mendilaharzu H, et al. Precocious
! c$ ]: \# l6 spuberty in children with tumours of the suprasellar pineal
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g# O, O( @8 O8 Eareas: organic central precocious puberty. Acta Paediatr.
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3 f! E" H. @ ~' H3. Lee PA. Puberty and its disorders. In: Lifshitz F, ed.
' j) m: O: Q9 p# H0 g6 QPediatric Endocrinology. 4th ed. New York, NY: Marcel- e( \$ A6 H4 c$ A9 T
Dekker Inc; 2003:211-238.0 c' V1 E7 v2 y; e9 ]* o. C' B6 x2 l
4. Yu YM, Punyasavatsu N, Elder D, D’Ercole AJ. Sexual
, z5 H! Z3 |: u) l$ d! p3 bdevelopment in a two-year-old boy induced by topical
4 [! K5 a0 A/ _: N+ Jexposure to testosterone. Pediatrics. 1999;104:e23.
2 w' I" ~; W, w. l. u5. Greulich WW, Pyle SI, eds. Radiographic Atlas of
5 ^# N* f5 [; m6 L( i; O7 j% iSkeletal Development of the Hand and Wrist. 2nd ed.9 ?, [5 H" k8 l {
Stanford, CA: Stanford University Press; 1959.; I2 J/ C) d: Z% ~
6. Physicians’ Desk Reference. Androgel 1% testosterone,3 x9 U$ e1 \: i+ |+ v( u. U
Unimed Pharmaceutical Inc. Montvale, NJ: Medical
# ?6 S$ J: W+ ], KEconomics Company, Inc; 2004:3239-3241.
0 L$ g* Q3 l+ Z2 y5 W& z7. Klugo RC, Cerny JC. Response of micropenis to topical
7 G4 B9 {) s% X0 ftestosterone and gonadotropin. J Urol. 1978;119:& f5 R, L7 h) S
667-668.
8 O$ m; f4 n+ F) t; {8. Guthrie RD, Smith DW, Graham CB. Testosterone% P; Z. N# f* X2 h
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